CN101066924B - 2-hexyl-3-hydroxy-5-R1Oxyhexadecanoic acid R2ester, preparation method and application thereof for preparing weight-reducing medicine orlistat - Google Patents

2-hexyl-3-hydroxy-5-R1Oxyhexadecanoic acid R2ester, preparation method and application thereof for preparing weight-reducing medicine orlistat Download PDF

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CN101066924B
CN101066924B CN2007100417857A CN200710041785A CN101066924B CN 101066924 B CN101066924 B CN 101066924B CN 2007100417857 A CN2007100417857 A CN 2007100417857A CN 200710041785 A CN200710041785 A CN 200710041785A CN 101066924 B CN101066924 B CN 101066924B
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马大为
吴清泉
徐鹏
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention is compound (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R1-oxy hexadecyl carboxylic acid R2 ester and its synthesis process and application in preparing orlistat as slimming medicine. The present invention prepares the ultimate product orlistat with (S)-chloroepoxy propane as initial material and through the first five reaction steps to obtain optically active intermediate, and the subsequent stereo selective reduction, alpha position alkylation, condensation with side chain amino acid and other reactions. The process is simple, easy to operate and suitable for industrial production.

Description

2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2Ester, preparation method and be used to prepare the purposes of slimming medicine orlistat
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to new synthetic method, by name more specifically to preparation chemistry: (S)-2-formamido group-4-methyl-valeric acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxygen-2-trimethylene oxide] methyl]-novel synthesis of the slimming medicine orlistat of dodecane ester; The present invention relates to the new intermediate of a class of orlistat, its preparation method and be used to prepare the purposes of orlistat.
Background technology
Orlistat (Orlistat) is a kind of lipase inhibitor.It forms the intermediate of non-activity with gi tract lipase in the presence of biliary salts, enzyme is produced irreversible inhibition, thereby weaken the digestion and the absorption of fat, makes to continue in the enteron aisle to be in the oil phase state, cholesterol is isolated and through defecate.Orlistat (Orlistat) is used for the treatment of Bariatric on April 23rd, 1999 by the drugs approved by FDA listing, and commodity are called Sai Nike (Xenical).
Chinese patent ZL97109032.1 has reported a kind of method by dish fermentative Production lipase statin.The yield of this method and production efficiency are not high, have caused the production cost of orlistat higher.
At present existing a plurality of synthetic patents at orlistat.
Summary of the invention
The purpose of this invention is to provide a kind of (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2The compound of ester is the important intermediate of synthetic slimming medicine orlistat.
Purpose of the present invention also provide a kind of above-mentioned (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2The synthetic method of the compound of ester.
Another object of the present invention provide a kind of above-mentioned (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2The use of a compound of ester is used to prepare the slimming medicine orlistat.
The present invention finally provides one, and route is succinct, reagent is cheap, lower-cost method for synthesizing orlistat.
In order to address the above problem, provide a kind of synthetic slimming medicine orlistat important intermediate (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2The compound of ester.
Preparation method of the present invention can adopt the tenth to 12 step in the step as described below, also may further include a step or the multistep in preceding nine steps in the following steps, for example the 9th to 12 step, in the 8th to 12 step, the 7th to 12 goes on foot, the the 6th to 12 step, the the 5th to 12 step, the 4th to 12 step, the 3rd to 12 step, second to 12 step or first to 12 step, the concrete reaction conditions of recommending is as described below.
For example: method of the present invention can be to be reacted with benzene sulfonyl chloride in organic solvent by compound (11); generate to close cyclic cpds (12), generate the compound (13) of deprotection through catalytic hydrogenation, again with formic acid, aceticanhydride mixture or arboxylic acid acid anhydride generation formylation reaction obtain as shown in the formula the target product orlistat shown in (I).The concrete reaction conditions of recommending is as described below.
Figure GFW00000039940600021
Guan Huanqian can further comprise by compound (10) in organic solvent, and the step that de-ester reaction obtains compound (11) takes place under the organic acid effect; Can comprise further also by compound (9) that in organic solvent under the room temperature condition, (for example N goes up R with amino acid fragment 3The leucine that replaces), DCC/DMAP obtains the step of compound (10) through condensation reaction generation selective esterification; Can comprise further also by compound (8) that under organic bases and the effect of negative ion stabilization reagent in organic solvent, under-90～10 ℃, with RX the step that α position alkylation obtains the compound (9) that carbonyl α position replaces takes place, wherein X is iodine or bromine, R is C 6Saturated or undersaturated alkyl, and when R be C 6Unsaturated alkyl the time, further to generate R through catalytic hydrogenation be C to the compound that above-mentioned carbonyl α position is replaced 6The substitution product (9) of saturated hydrocarbyl; Also can further comprise by compound (7) in organic solvent, under-78～20 ℃,, induce the step of the dihydroxyl compound (8) that generates cis with hydroborating agents generation selective reduction.The concrete reaction conditions of recommending is as described below.
Method of the present invention also can further comprise by compound (6) under the highly basic effect on above-mentioned step basis by compound (7) preparation target product orlistat, in the organic solvent with acetic ester generation condensation reaction, obtain the product that carbochain is extended, be compound (7), the step of 5-hydroxyl-3-oxo hexadecanoic acid tert-butyl ester; Also can further comprise by compound (5) in organic solvent, under the thionyl chloride effect with pure R 5OH obtains the product (6) of esterification, i.e. the step of 3-hydroxyl tetradecane acid ester through condensation reaction; Also can further comprise by compound (4) under the effect of organic solvent and alkali,, generate the step of compound (5) through cyan-hydrolysis with the hydrogen peroxide reaction.Method perhaps of the present invention also can further comprise the step that is obtained compound (7) by compound (4) in organic solvent with the monobromo-acetic acid ester through the Blaise reaction on above-mentioned step basis by compound (7) preparation target product orlistat.The concrete reaction conditions of recommending is as described below.
Method of the present invention also can further comprise by compound (3) in organic solvent on above-mentioned step basis by compound (4) preparation target product orlistat, with the NaCN reaction, simultaneously with acid control pH value, obtains the step of compound (4); Can comprise further that also (the S)-epoxy chloropropane that adopts high optical activity and cheaply be easy to get is a starting raw material, under CuI catalysis, obtain compound (2) through ring-opening reaction taking place, encircle and obtain the step of epoxy compounds (3) in alkaline condition ShiShimonoseki with decane metal-salt reagent (for example Grignard reagent).The concrete reaction conditions of recommending is as described below.
The structural formula of concrete technology of recommending and above-mentioned each compound is as follows:
The first step, (S)-epoxy chloropropane under the CuI catalytic condition with metal alkylide salt reagent effect generation ring-opening reaction.Reaction formula is for example:
Figure GFW00000039940600031
Described metal alkylide salt reagent can be the chloroparaffin of decane metal-salt, the Grignard reagent of bromo alkane or corresponding lithium reagent, and reaction obtains the adjacent hydroxy halogeno alkane of long-chain of open loop.The organic solvent that reacts used is recommended tetrahydrofuran (THF), toluene, methyl alcohol or ethanol, further recommends tetrahydrofuran (THF) and/or toluene.Recommending the compound (1) and the reaction mol ratio of decane metal-salt reagent is (1～1.5): 1, further recommend (1.1～1.2): and 1, temperature of reaction is controlled at-78～25 ℃.Reaction times recommended 4～10 hours.Wherein the affinity owing to Grignard reagent is stronger, if direct and epichlorohydrin reaction, the carbon atom that the direct attack of meeting links to each other with the chlorine atom, thus directly generate and the opposite product of compound 3 configurations.Side reaction does not take place and gets purpose to reach in the CuI that therefore adds catalytic amount in reaction, and control reaction temperature can make that Grignard reagent is active to be reduced.The compound of recommending (1) is 1 with the consumption mol ratio of CuI: (0.001～0.01).Through aforesaid operations, products therefrom with delivered the situation that the data contrast finds no racemization.
In addition, the gained intermediate need not purifying in this reaction, can directly generate epoxy compounds at alkaline condition ShiShimonoseki ring, and reaction can be carried out in alcoholic solution, after simple process, can obtain highly purified compound 3 through underpressure distillation again.
Second step, products therefrom (3) and NaCN reacting generating compound (4).Be reflected in the organic solvent and carry out.Reaction formula is for example:
Figure GFW00000039940600041
This step reaction is recommended to make solvent with methyl alcohol or ethanol, and with NaCN reacting generating compound 4, temperature of reaction need be controlled at room temperature～60 ℃, recommends about 50 ℃.Reaction times recommended 8～12 hours.Compound 3 recommends 1 with the mol ratio of NaCN: (1～1.5).Because following side reaction when it is dripped, takes place in the strong basicity of the NaCN aqueous solution easily in the alcoholic solution of compound 3.
Figure GFW00000039940600042
By the pH value of conditioned response, can reduce the ratio of by product, effect is best when PH is between 10-12, and the acid of wherein regulating PH can be sulfuric acid, hydrochloric acid, citric acid, acetic acid etc.; In addition, be reflected under 50 ℃ of conditions more suitable.
The 3rd step, above products therefrom (4) in organic solvent, with hydrogen peroxide, for example sodium hydroxide or potassium hydroxide aqueous solution reaction of alkali generates hydrolysate (5).Reaction formula is for example:
Figure GFW00000039940600043
Temperature of reaction can be recommended reflux between 0～100 ℃, the effect that wherein refluxes is best.Reaction times recommended 5～12 hours.Compound (4) and H 2O 2, alkali mol ratio be 1: (1～8): (1～8).Described organic solvent is recommended methyl alcohol or ethanol.
The 4th step, with the acid (5) of gained in organic solvent, at ambient temperature with thionyl chloride, pure R 5The product (6) that condensation reaction generates esterification, wherein R take place in OH 5Represent C 1～C 6Alkyl, be recommended as methyl.Compound (5) is recommended as 1 with the mol ratio of thionyl chloride, alcohol: (1～3): (1～20), temperature of reaction is recommended as room temperature, and the reaction times recommended 2～12 hours, wherein organic solvent is recommended methyl alcohol, ethanol or Virahol, reaction can use the alcohol of esterification as solvent;
Reaction formula is for example:
Figure GFW00000039940600051
In the 5th step, the compound of gained (6) in the organic solvent, is recommended under-78 ℃～0 ℃ the cold condition, with acetic ester CH under the organic bases effect 3COOR 4Condensation reaction takes place obtain 5-hydroxyl-3-carbonyl ester (7).R wherein 4Represent C 1～C 6Alkyl, be recommended as the tertiary butyl.Reaction formula is for example:
Figure GFW00000039940600052
Described organic bases is recommended LDA, LiHMDS or NaHMDS, and described solvent is recommended as tetrahydrofuran (THF) or ether, and the mol ratio of described acetic ester, alkali and compound (6) is recommended as (6～1): (6～1): 1, further recommended 4: 4: 1; Reaction times recommended 0.5～2 hour.
For synthesizing of above-claimed cpd (7), another kind of comparatively easy method is by following reaction:
Directly with activatory zinc powder and compound 6, bromacetate BrCH 2COOR 4The Blaise reaction takes place under catalytic condition.R 4As previously mentioned, in the Blaise reaction of cyano compound (4) and bromo-acetic acid tert-butyl, described catalyzer is ultrasonic wave or methanesulfonic, the mol ratio of described zinc powder, bromacetate, catalyzer and cyano compound (4) recommends to be followed successively by (8～1): (4～1): (0～0.01): 1, further recommended 4: 2: 1; Temperature of reaction is recommended room temperature～60 ℃, this temperature of reaction outbalance, and extremes of temperature is all bad to the influence of reaction, and for bromo-acetic acid tert-butyl, 50 ℃ for suitable; Described solvent is recommended tetrahydrofuran (THF), and the reaction times recommended 1～8 hour.
In the 6th step, above-mentioned gained compound (7) is in organic solvent, with the dihydroxyl compound (8) of the reaction induced generation cis of hydroborating agents.Temperature of reaction is recommended-78 ℃～20 ℃, further recommend-78 ℃, described organic solvent is recommended tetrahydrofuran (THF), temperature of reaction-78 ℃～20 ℃, compound (7) is recommended as 1 with the reaction mol ratio of hydroborating agents: (1～3), described hydroborating agents is recommended diethyl methoxyl group boron/sodium borohydride, zinc borohydride or triethyl-boron/sodium borohydride, and the reaction times recommended 4～12 hours;
Reaction formula is for example:
Figure GFW00000039940600061
R 4As previously mentioned.This step reaction needs carry out under cold condition, and isomer increased when temperature was high, and it is the most suitable to be reflected under-78 ℃ the cold condition, and the ee value is greater than 99%.
The 7th step, the Stereoselective alkylation of compound (8) α position.
Figure GFW00000039940600062
α position alkylated reaction in organic solvent, takes place with RX and generates the compound that carbonyl α position replaces, wherein R under organic bases and the effect of negative ion stabilization reagent in gained compound (8) 4As previously mentioned, X is iodine or bromine, and R is C 6Saturated or undersaturated alkyl; And when R is C 6Unsaturated alkyl the time, further to generate R through catalytic hydrogenation be C to the compound that above-mentioned carbonyl α position is replaced 6The substitution product (9) of saturated hydrocarbyl, promptly R is C 6H 13Described organic bases is recommended LDA, LiHMDS or NaHMDS, further recommend LDA, solvent is recommended tetrahydrofuran (THF) or toluene, temperature of reaction is recommended-90～10 ℃, described negative ion stabilization reagent is recommended HMPA or HMPT, and the mol ratio of RX and compound (8) is recommended (1～4): 1, and described R recommends normal hexane base, 2-hexenyl or 2-thiazolinyl 5-hexin base, the mol ratio of described organic bases and compound (8) is recommended (1～8): 1, and the reaction times recommended 5～12 hours; Reaction recommends to use the dry tetrahydrofuran solution of excessive n-BuLi/ diisopropylamine, alkylating reagent and HMPA to carry out between-90 ℃～10 ℃.Alkylating reagent RX can be iodohexane, bromohexane, 6-bromo-4-alkynes hexene etc.The temperature of reaction preference and reaction has much relations.Temperature is low more, selectivity is good more, but simultaneously, reaction compares slow.When temperature was too high, side reaction increased, and optimum temperature for example-20 ℃.
In the 8th step, the selective esterification reaction of dihydroxyl compound can be used the method for DCC/DMAP.Compound (9) under the room temperature condition, is gone up R with N in organic solvent 3The leucine, the DCC/DMAP that replace obtain compound (10) through condensation reaction generation selective esterification; R wherein 2As previously mentioned, R 3Be amino protecting group, recommend carbobenzoxy-(Cbz) etc.Described organic solvent is recommended DMF or methylene dichloride, further recommends DMF, and temperature of reaction is recommended room temperature, and compound (9) is gone up R with N 3The leucic mol ratio that replaces is recommended (3～1): 1, and wherein DMAP and N go up R 3The leucic mol ratio that replaces is recommended (3～1): 1, and DCC and N go up R 3The leucic mol ratio that replaces is recommended (3～1): 1, the reaction times recommended 2～16 hours, reaction formula for example:
Figure GFW00000039940600071
R wherein 3, R 4As previously mentioned.
The method of DCC/DMAP is used in this reaction, it is 2: 1 preferably wherein by adjusting dihydroxyl compound and N-carbobenzoxy-(Cbz)-leucic mol ratio, DMAP and N-carbobenzoxy-(Cbz)-leucic mol ratio is 1: 1 a method, reach and reduce by two hydroxyls and esterification all takes place get purpose, thereby realize optionally esterification.In the 9th step, gained compound (10) issues unboiled water in the organic acid effect and separates reaction and take off ester and generate required compound (11) in organic solvent; Described organic solvent is recommended haloalkane such as methylene dichloride; trichloromethane etc.; temperature of reaction is recommended room temperature; described organic acid is recommended trifluoroacetic acid or tosic acid; and the organic acid concentration of compound (10) reaction is recommended between 5～20%; reaction times recommended 2～16 hours, and described amino protecting group is carbobenzoxy-(Cbz) or tert-butoxycarbonyl.Described compound (10) and organic acid mol ratio be recommended as 1: 1～and 2.
Reaction formula is for example:
Figure GFW00000039940600072
R 3, R 4As previously mentioned.The reaction agents useful for same is recommended as the dichloromethane solution of trifluoroacetic acid.
In the tenth step, idic acid (11) with the benzene sulfonyl chloride reaction, generates and closes cyclic cpds (12) in organic solvent; Described organic solvent is recommended pyridine, and temperature of reaction is recommended 0 ℃～20 ℃, and compound (11) recommends 1 with benzene sulfonyl chloride reaction mol ratio: (1.5～2), the reaction times recommended 1～2 hour, and reaction system is recommended anhydrous.Reaction formula is for example:
Figure GFW00000039940600081
R wherein 3As previously mentioned.
In the 11 step, compound (12) generates the compound (13) of deprotection by catalytic hydrogenation deaminize protecting group.Be recommended in Pd/C and H 2Catalytic hydrogenation takes place down in effect; Described step 2) in, described organic solvent is recommended methyl alcohol, ethanol, ethyl acetate or tetrahydrofuran (THF), and temperature of reaction is recommended 30 ℃～40 ℃, and reaction pressure is recommended 5～20atm, compound (12) recommends 1 with the mol ratio of Pd/C: (0.005～0.02), and the reaction times recommended 4～12 hours;
Reaction formula is for example:
Figure GFW00000039940600082
R 3As previously mentioned.
The 12 step, compound (13) and formic acid, aceticanhydride mixture or with arboxylic acid acid anhydride generation formylation reaction, generate compound (14); Temperature of reaction is recommended room temperature, and compound (13) recommends 1 with the mol ratio of formic acid, aceticanhydride: (1.5～2), the reaction times recommended 1～4 hour.Reaction formula is for example:
Figure GFW00000039940600083
R 3As previously mentioned.Reaction preferably mixes the method that generates the arboxylic acid acid anhydride by formic acid with aceticanhydride, generate target molecule with substrate-function.
Aforementioned LDA represents lithium diisopropyl amido, and DCM represents methylene dichloride, and THF represents tetrahydrofuran (THF), and TFA represents trifluoroacetic acid, Et 2BOMe represents diethyl methoxyl group boron, and LiHMDS represents hexamethyl two silica-based amido lithiums, NaBH 4Represent sodium borohydride, NaHMDS represents sodium hexamethyldisilazide, and DCC represents dicyclohexylcarbodiimide, and HMPA represents hexamethylphosphoramide, and HMPT represents the hexamethyl phosphoramidite, and DMAP represents 4-dimethyl amine yl pyridines, and CbZ represents carbobenzoxy-(Cbz).Aforesaid aq. represents the aqueous solution.
Obtained new intermediate in the preparation process of the present invention, can be used for preparing orlistat, these new midbody compounds be (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2The compound of ester, its structural formula is as follows:
R in the formula 1Represent H or
Figure GFW00000039940600092
R wherein 3Represent amino protecting group, preferred carbobenzoxy-(Cbz) or tertiary butyloxycarbonyl acyl group; R 2Represent H or C 1～C 6Alkyl.
The preferred construction formula is as follows:
Figure GFW00000039940600093
R wherein 3Represent amino protecting group, preferred carbobenzoxy-(Cbz) or tertbutyloxycarbonyl.
The 6th at least two step or the polystep reactions that go on foot in the reaction of the 9th step in the technology of the concrete recommendation that above-mentioned new intermediates preparation can be aforementioned synthetic orlistat, for example the 6th step and the 7th goes on foot, perhaps the 6th went on foot for the 8th step, perhaps the 6th went on foot for the 9th step.Above-mentioned new intermediates preparation can further include at least one step or polystep reaction in the first step to the five steps reaction in the technology of concrete recommendation of aforementioned synthetic orlistat in aforementioned preparation method the 6th at least two steps or polystep reaction that go on foot in the 9th step.The reaction conditions of recommending as previously mentioned.
Above-mentioned new midbody compound can be used for preparing orlistat, and the preparation method of recommendation can be that the tenth in the technology of concrete recommendation of aforementioned synthetic orlistat went on foot for the 12 step.The reaction conditions of recommending as previously mentioned.
The invention provides a kind of new midbody compound, preparation method and purposes of synthetic orlistat.This midbody compound can be used for synthetic orlistat, and step is succinct, and each step reaction easy handling is easy to industrialization.The total recovery in 10 steps of orlistat synthetic route of the present invention is 2.0%, and wherein compound (7) is generated through single step reaction by compound (4).This route has the three-step reaction yield that corresponding raising is all arranged after the amplification scale, probably all improves about 10%.So far, the reagent price height that other chemical synthesis routes are used, route is long, and total recovery is all not as route of the present invention.
Embodiment
(will help to understand the present invention by following example, but not limit content of the present invention.)
The first step
Figure GFW00000039940600101
Get a 100ml three-necked bottle, after the baking ventilation, reach the anhydrous and oxygen-free operation.Successively to wherein add magnesium chips (2.5g, 0.104mol), anhydrous tetrahydro furan 18ml, the glycol dibromide of catalytic amount (0.05ml).With above-mentioned reaction as in the water-bath, dripping bromine decane (20.8ml, 20ml anhydrous toluene solution 98mmol), and temperature control remains on about 40 ℃.After dropwising, stirring at room 0.5h, temperature rising reflux 0.5h then, this moment, reaction solution was stillness of night shape.Dry THF/Toluene represents anhydrous tetrahydrofuran (THF)/toluene solvant in the formula.
Other gets a 100ml three-necked bottle, the anhydrous and oxygen-free operation.Add successively cuprous iodide (154mg, 0.81mmol), (S)-epoxy chloropropane (7.04ml, 90mmol), dry toluene 5ml.Reaction is cooled to-10 ℃, and the Grignard reagent for preparing is previously slowly dropped in the reaction solution, and the time surpasses 45min.After dropwising, the dry toluene of 10ml * 2 is integrated with in the reaction after swinging and washing dropping funnel.Temperature control is about 0 ℃, and reaction 0.5h rises to room temperature then, continues reaction 5h.The point plate is followed the tracks of, and reacts no considerable change, so to wherein adding the 10ml concentrated hydrochloric acid, temperature control is below i0 ℃.Reaction solution is changed into blackish green by original grey black, this moment, pH value was less than 1.Revolve to steam and remove tetrahydrofuran (THF), in residuum, add 20ml water, demixing.Water merges organic phase then with toluene 10ml * 2 back extractions.
In organic phase, add 19ml methyl alcohol and 8ml 48% aqueous sodium hydroxide solution, reaction stirring at room 5h.Revolve to steam and remove methyl alcohol, residue organic phase separatory, water merges organic phase after the toluene back extraction of 10ml * 2.Organic phase is after washing, and drying is filtered, revolve after the steaming thick product.After the underpressure distillation, get straight product 13.0g, productive rate 73.1%.
This reaction can be (1～1.5) in the reaction mol ratio of compound (1) and decane metal-salt reagent also: 1, and temperature of reaction is carried out under-78～25 ℃, and the reaction times is 4～10 hours.
1HNMR(300Hz，CDCl 3)δ2.92-2.88(m，1H)，2.76-2.73(t，1H)，2.48-2.45(q，1H)，1.56-1.39(m，4H)，1.39-1.21(m，16H)，0.90-0.86(t，3H)；ESI-MS?m/z?198(M +)。
Second step
Figure GFW00000039940600111
(990mg 5mmol) is dissolved in the 4ml methyl alcohol, drips 29% sodium cyanide solution (sodium cyanide 294mg, 6mmol are dissolved in 0.72ml water) then in wherein to get above-mentioned product.During dropping, white solid is separated out, and keep PH 11 about again to wherein dripping vitriol oil 0.11ml synchronously this moment, and the reaction temperature control is about 50 ℃.Behind the 10h, the reflecting point plate, raw material point disappears.The reaction nature is cooled to room temperature, to wherein adding 10ml saturated aqueous common salt and ethyl acetate.Water merges with original organic phase after the ethyl acetate back extraction, merge organic interdependent time after the saturated common salt washing, drying, suction filtration, revolve after the steaming thick product, thick product can directly be cast the step reaction.Thick product gets the 951mg pure products, productive rate 84.5% through behind the column purification.
1HNMR(300Hz，CDCl 3)δ4.00-3.90(m，1H)，2.62-2.45(dq，2H)，2.02-2.00(d，1H)，1.57-1.50(m，1H)，1.37-1.20(m，19H)，0.94-0.83(t，3H)；ESI-MS?m/z?225(M +)。
This reaction also can be carried out 8～12 hours reaction times between room temperature～60 ℃.
The 3rd step
Figure GFW00000039940600112
(634mg 2.82mmol) fully is dissolved in the 10ml methyl alcohol, then to the sodium hydroxide solution of hydrogen peroxide that wherein adds 2ml 30% and 2ml 48% with the gained prussiate.Adularescent solid generation immediately in the reaction, reaction reflux 8h, some board raw material point disappears behind the 8h.Reaction solution is reduced to room temperature naturally, to wherein dripping 40ml 1N dilute hydrochloric acid, regulate pH value less than 1, this moment, the adularescent needle-like solid generated.Suction filtration, solid retained, and wash twice with water, drain.The gained solid is dissolved again with ethyl acetate, and through the saturated common salt water washing, drying, suction filtration is spin-dried for.After oil pump is drained, obtain white solid 642mg, productive rate 93.0%.
1HNMR(300Hz，CDCl 3)δ4.07-4.02(m，1H)，2.63-2.44(m，2H)，1.55-1.39(m，3H)，1.27(m，17H)，0.91-0.87(t，3H)；ESI-MS?m/z?267(M+Na +)。
This reaction also can be between 0～100 ℃, 5～12 hours reaction times.
The 4th step
Figure GFW00000039940600121
(488mg 2mmol) is dissolved in the 5ml methyl alcohol, is cooled to about 0 ℃, and (reaction is stirred and spent the night for 0.3ml, 4mmol) sulfur oxychloride to wherein dripping then to get the step products therefrom.Next day, raw material point disappears, and revolves to steam to remove to desolvate, and gained oily matter is dissolved again with ethyl acetate, and organic phase is successively through saturated sodium bicarbonate solution, the saturated common salt water washing, drying, suction filtration, be spin-dried for product 380mg, productive rate 73.6%.This product need not to handle, and can directly drop into next step.
1H?NMR(300Hz，CDCl 3)δ4.03-3.98(m，1H)，3.72(s，3H)，2.89-2.87(d，1H)，2.56-2.37(m，2H)，1.26(m，20H)，0.90-0.86(t，3H)；ESI-MS?m/z?281(M+Na +)。
This reaction also can be in the mol ratio 1 of compound (5) and thionyl chloride, alcohol: (1～3): between (1～20), temperature is to carry out under the room temperature condition, 2～12 hours reaction times.
The 5th step
Figure GFW00000039940600122
Anhydrous and oxygen-free operation gets that (3.5ml, 5.6mmol) n-butyllithium solution of 1.6M drips in (0.783ml, 5.6mmol) in the 4ml anhydrous tetrahydrofuran solution of Diisopropylamine, temperature control is a little less than 0 ℃.Keep this temperature, behind the reaction 15min, be cooled to-78 ℃, then with (0.76ml, 5.6mmol) tert-butyl acetate adds wherein.The gained reaction solution is at-78 ℃ of following reaction 45min, then will (290mg, 1.12mmol) compound 6 is dissolved in the 3ml anhydrous tetrahydro furan, and it is dropped in the reaction, keeps temperature-78 ℃.Continue to keep low-temp reaction 1h, slowly rise to room temperature then and surpass 2h.
Reaction is reduced to 0 ℃, and adding 2ml 1N hydrochloric acid reacts with cancellation.Reaction is divided into two-phase, and water is with ethyl acetate 5ml back extraction, and the organic phase of merging is used saturated sodium bicarbonate 10ml successively, and saturated aqueous common salt 10ml washes, drying, suction filtration, be spin-dried for flaxen thick product.Cross post and get straight product 310mg, productive rate 80.9%.
1HNMR(300Hz，CDCl 3)δ4.11-4.07(m，1H)，3.40-3.39(d，1H)，2.84-2.58(m，2H)，1.52-1.45(m，9H)，1.44-1.38(m，2H)，1.37-1.29(m，20H)，0.91-0.86(t，3H)；ESI-MS?m/z?365(M+Na +)。
This reaction also can be between-78 ℃～0 ℃, and the mol ratio of described acetic ester, alkali and compound (6) is (6～1): (6～1): carry out 0.5～2 hour reaction times under 1 the condition.
The 6th step
Figure GFW00000039940600131
The anhydrous and oxygen-free operation will (1.19g, 3.48mmol) compound 7 and 12ml anhydrous tetrahydro furan and 3.8ml anhydrous methanol thorough mixing.After waiting to be cooled to-78 ℃, get (3.83ml, 3.83mmol) diethyl oxygenation base B solution (1M in hexane) slowly drops in the above-mentioned reaction solution, and the gained mixture fully stirred 15 minutes after dropwising.Then to wherein add sodium borohydride (146mg, 3.83mmol), reaction maintains low temperature-78 ℃, continues to stir after 8 hours, some board raw material point disappears, and reacts to wherein adding the cancellation of 3.5ml acetate.Allow then and react nature appreciation room temperature, and add less water.Wait to revolve steam remove organic solvent after, with ethyl acetate extraction water twice, the organic phase of merging is successively through saturated sodium bicarbonate solution, the saturated common salt washing is dry then, suction filtration, after being spin-dried for thick product.After column chromatography for separation, get straight product 816mg, productive rate 71.6%, the ee value is greater than 99%.
This reaction also can be at-78 ℃～20 ℃, and compound (7) is 1 with the hydroborating agents mol ratio: carry out 4～12 hours reaction times under the condition of (1～3).
1H?NMR(300Hz，CDCl 3)δ4.24-4.20(m，1H)，3.92(s，1H)，3.92-3.85(m，1H)，3.53(s，1H)，2.40-2.38(d，1H)，1.55-1.51(m，2H)，1.45(s，9H)，1.32-1.24(m，21H)，0.88-0.84(t，3H)；ESI-MS?m/z?367(M+Na +)。
The 7th step
Will (0.76ml, 1.6M n-butyllithium solution 1.22mmol) be added drop-wise to that (0.19ml, 1.342mmol) in the 1.5ml anhydrous tetrahydro furan of Diisopropylamine, controlled temperature is about 0 ℃.Be reflected at 0 ℃ stir 0.5h after, will (105mg, 0.305mmol) the 2ml anhydrous tetrahydrofuran solution of compound 8 joins in the reaction, temperature control-78 ℃.After reaction remains on this temperature 1h, be warming up to-15 ℃, be cooled to-78 ℃ behind the 15min again.At this moment 0.58ml HMPA is added in the reaction solution, after low temperature keeps 10min, again with (0.33ml, iodohexane 0.915mmol) adds wherein.After reaction continues to remain on low temperature 2h, slowly rise to-20 ℃, keep this temperature 2h after, cancellation reaction.Add saturated ammonium chloride solution in reaction, regulate PH about 8, the reaction nature rises to room temperature.
Revolve to steam and remove tetrahydrofuran (THF), and with ethyl acetate aqueous phase extracted again, the gained organic phase is successively through saturated aqueous common salt, drying, and suction filtration is spin-dried for the thick product in back.After crossing the thick product of column purification, get required compound 79mg, productive rate 61.0%.
1HNMR(300Hz，CDCl 3)δ4.02-3.90(dm，2H)，3.23-3.20(d，1H)，2.52(s，1H)，2.36-2.29(m，1H)，1.71-1.48(m，5H)1.58-1.40(s，9H)，1.36-1.20(m，26H)，0.95-0.80(t，6H)；ESI-MS?m/z?451(M+Na +)。
This reaction also can be at-90～10 ℃, and the mol ratio of RX and compound (8) is (1～4): 1, and the mol ratio of described organic bases and compound (8) is (1～8): carry out 5～12 hours reaction times under 1 the condition.
The 8th step
Figure GFW00000039940600142
Will (2.48g, 5.79mmol) compound 9, and (657mg, 3.19mmol) dicyclohexylcarbodiimide is with (389mg, 3.19mmol) 4-dimethyl amine yl pyridines is dissolved in the anhydrous N of 5ml, in the dinethylformamide, solid is fully dissolved.With (769mg, 2.90mmol) leucine of N-carbobenzoxy-(Cbz) protection is dissolved among the 2ml, then it is slowly dropped in the above-mentioned reaction solution, after half an hour, dropwises.Room temperature fully stirs, and has solid to generate after two hours, and reaction is stirred and spent the night.Next day, after reaction solution concentrated, through column chromatography for separation, product colorless oil 1.08g that must be purer, productive rate 55.1%.
1HNMR(300Hz，CDCl 3)δ7.40-7.27(m，5H)，5.19-5.16(d，2H)，5.11-5.06(m，3H)，4.47-4.29(dm，1H)，3.59-3.53(m，1H)，3.06-3.03(d，1H)，2.30-2.23(m，1H)，1.65-1.49(m，9H)，1.49-1.40(m，9H)，1.38-1.21(m，25H)，0.94-0.90(t，6H)，0.86-0.74(t，6H)；ESI-MSm/z 698(M+Na +)。
This reaction also can be in compound (9), DMAP, and DCC and N go up R 3The leucic mol ratio that replaces is (3～1): (3～1): (3～1): carry out 2～16 hours reaction times under 1 the condition.
The 9th step
Compound 10 is dissolved in 10% trifluoracetic acid/methylene dichloride, about 0 ℃ of temperature of reaction, the some plate tracks to and reacts completely, and removal of solvent under reduced pressure can not separated and directly be carried out next step reaction.
1HNMR(300Hz，CDCl 3)δ7.40-7.26(m，5H)，5.20-5.17(d，2H)，5.11-5.06(m，3H)，4.47-4.31(dm，1H)，3.59-3.53(m，1H)，3.06-3.03(d，1H)，2.31-2.23(m，1H)，1.49-1.40(m，9H)，1.40-1.23(m，25H)，0.95-0.90(t，6H)，0.86-0.75(t，6H)；ESI-MS?m/z?642(M+Na +)。
This reaction also can be carried out 2～16 hours reaction times under organic acid concentration is 5～20% condition.
The tenth step
To go up step gained compound (30mg 0.0485mmol) is dissolved in the 1ml anhydrous pyridine, treat that raw material fully dissolves after, be cooled to about 0 ℃ with ice-water bath, in reaction system, drip the 0.2ml benzene sulfonyl chloride then, dropwise the back ambient temperature overnight and stir.Next day, TLC after detecting the raw material disappearance is spin-dried for reaction solvent.Again after dissolving with ethyl acetate, successively through the ammonium chloride saturated solution, the saturated common salt washing.Dry then, suction filtration is spin-dried for, and gets faint yellow oily thing.After column chromatography for separation, get straight product 14mg colorless oil, productive rate 48.1%.
1H?NMR(300Hz，CDCl 3)δ7.36(m，5H)，5.11(m，3H)，5.01-4.98(m，1H)，4.39-4.23(dm，2H)，3.24-3.19(m，1H)，2.03-1.98(t，2H)，1.80-1.63(m，3H)，1.57-1.40(m，4H)，1.28-1.25(m，30H)，0.98-0.94(m，6H)，0.90-0.86(m，6H)；ES?I-MS?m/z?624(M+Na +)。
This reaction also can be between 0 ℃～20 ℃ of temperature of reaction, compound (11) and benzene sulfonyl chloride reaction mol ratio 1: carry out 1～2 hour reaction times under the condition of (1.5～2).
The 11 step
Will (14mg, 0.0233mmol) above-mentioned products therefrom is dissolved in the 2ml methyl alcohol, adds 10% palladium carbon 10mg, and after fully stirring, reaction places under the hydrogen pressure of 15atm, and 40 ℃ of temperature were reacted 5 hours.The point plate removes by filter catalyzer after detecting the raw material disappearance.After treating that solvent is drained, can directly throw in next step reaction.
This reaction also can be 30 ℃～40 ℃ of temperature of reaction, reaction pressure 5～20atm, the mol ratio 1 of compound (12) and Pd/C: carry out 4～12 hours reaction times under the condition of (0.005～0.02).
The 12 step
Figure GFW00000039940600162
Above-mentioned products therefrom is dissolved in the 1ml anhydrous tetrahydro furan, adds arboxylic acid acid anhydride (can by formic acid and aceticanhydride mixed) 0.5ml, room temperature after 2 hours raw material reaction complete, add 2ml saturated aqueous common salt cancellation reaction.Use ethyl acetate extraction water twice then, after the gained organic phase merges, drying, suction filtration gets thick product off-white color solid after being spin-dried for.Behind column chromatography purification, can get the finished product white solid 7mg, above two steps merge productive rate 58.3%.
1H?NMR(300Hz，CDCl 3)δ8.22(s，1H)，5.91(d，1H)，5.04-5.01(m，1H)，4.71-4.69(m，1H)，4.29-4.28(m，1H)，3.22(m，1H)，2.23-2.01(m，2H)，1.81-1.26(m，33H)，0.98-0.96(d，6H)，0.86-0.83(m，6H)；ESI-MS m/z518(M+Na +)。
This reaction also can be in room temperature, and compound (13) is 1 with the mol ratio of formic acid, aceticanhydride: (1.5～2): carry out 1～4 hour reaction times under the condition of (1.5～2).
Complement operation
Figure GFW00000039940600171
In the single neck bottle of 25ml, add 310mg compound 4, and it is dissolved in the 2ml anhydrous tetrahydro furan.Other gets the single neck bottle of a 25ml, and (135mg, 2.08mmol), the 1ml anhydrous tetrahydro furan adds catalytic amount (3～5) methanesulfonic, reflux 10 minutes then in mixture to wherein adding zinc powder.Then the drips of solution with the compound 4 of front adds in the reaction system, drips slowly in reaction that (return time surpasses half an hour for 0.22ml, 1.66mmol) bromo-acetic acid tert-butyl again.
Reaction continued 1 hour, reduced to room temperature then, and the 3N hydrochloric acid soln is added wherein cancellation reaction, regulated about pH value to 1.Wait to revolve steam remove tetrahydrofuran (THF) after, with ethyl acetate aqueous phase extracted again repeatedly, merge organic phase through saturated sodium bicarbonate solution, the saturated common salt washing, drying, suction filtration, after being spin-dried for thick product.Through column chromatography purification, can get straight product 180mg, productive rate 50.4%.
1HNMR(300Hz，CDCl 3)δ4.11-4.07(m，1H)，3.40-3.39(d，1H)，2.84-2.58(m，2H)，1.52-1.45(m，9H)，1.44-1.38(m，2H)，1.37-1.29(m，20H)，0.91-0.86(t，3H)；ESI-MS?m/z?365(M+Na +)。
This reaction can be ultrasonic wave or methanesulfonic at catalyzer also, and the mol ratio of described zinc powder, bromacetate and cyano compound (4) is (8～1): (4～1): 1, to carry out under the condition of temperature of reaction room temperature～60 ℃, and the reaction times recommended 1～8 hour.
In the foregoing description, described dry THF represents anhydrous tetrahydro furan, and N-Cbz-Leucine represents N-carbobenzoxy-(Cbz)-leucine, and Pyr represents pyridine, and DMF represents dimethyl formamide.Other unless otherwise indicated, all as previously mentioned.

Claims (8)

1. one kind (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2The compound of ester, its structural formula is as follows:
Figure FFW00000039940400011
R in the formula 1Representative
Figure FFW00000039940400012
R wherein 3Represent amino protecting group; R 2Represent H or C 1～C 6Alkyl; Described amino protecting group is carbobenzoxy-(Cbz) or tert-butoxycarbonyl.
2. as compound according to claim 1, it is characterized in that this structural formula of compound is as follows:
Figure FFW00000039940400013
R wherein 3According to claim 1.
One kind as claimed in claim 1 (2S, 3S, 5S)-2-hexyl-3-hydroxy-5-R 1Oxygen base ten hexacarboxylic acid R 2The synthetic method of the compound of ester is characterized in that comprising the steps 1)～2) or step 1)～3) two kinds of synthetic methods:
1), under-90～10 ℃ of organic solvent neutralizations, α position alkylated reaction takes place with RX and generates the compound that carbonyl α position replaces under organic bases and the effect of negative ion stabilization reagent in compound (8), wherein X is iodine or bromine, R is C 6Saturated or undersaturated alkyl; When R is C 6Unsaturated alkyl the time, it is C that the compound that above-mentioned carbonyl α position is replaced generates R through catalytic hydrogenation 6The substitution product (9) of saturated hydrocarbyl; Described negative ion stabilization reagent is HMPA or HMPT, the mol ratio of RX and compound (8) is 1～4: 1, the mol ratio of described organic bases and compound (8) is 1～8: 1, and a reaction times 5-12 hour HMPA represents hexamethylphosphoramide, and HMPT represents the hexamethyl phosphoramidite;
2), in organic solvent and under the room temperature condition, step 1) gained compound (9) and N go up R 3The leucine, the DCC/DMAP that replace obtain compound (10) through 2～16 hours condensation reaction generation selective esterifications; Described compound (9) is gone up R with N 3The leucic mol ratio that replaces is 3～1: 1; The leucic mol ratio that DMAP and N-replace is 3～1: 1, and DCC and N go up R 3Substituent leucic mol ratio is 3～1: 1; Wherein DCC represents dicyclohexylcarbodiimide, and DMAP represents 4-dimethyl amine yl pyridines;
3), in organic solvent and under the room temperature, step 2) gained compound (10) issues unboiled water in the organic acid effect and separates reaction and take off ester and generate compound (11); Described organic acid is trifluoroacetic acid or tosic acid, and the organic acid concentration of compound (10) reaction is between the 5-20%, and compound (10) is 1: 1～2 with the organic acid mol ratio; Reaction times is 2～16 hours;
Described compound (8)～(11) structural formula is as follows:
Figure FFW00000039940400021
R wherein 4Represent C 1～C 6Alkyl, R 3According to claim 1.
4. synthetic method as claimed in claim 3, the following step of employing that it is characterized in that described compound (8) is synthetic: under-78～20 ℃ of organic solvent neutralizations, compound (7) and hydroborating agents generation selective reduction reaction, induce the dihydroxyl compound (8) that generates cis, compound (7) is 1: 1～3 with the reaction mol ratio of hydroborating agents, described hydroborating agents is diethyl methoxyl group boron/sodium borohydride, zinc borohydride or triethyl-boron/sodium borohydride, 4～12 hours reaction times; Wherein, compound (8) and R 4As described in claim 3, the structural formula of compound (7) is as follows:
Figure FFW00000039940400022
5. method as claimed in claim 4 is characterized in that compound (7) adopts following step 5), step 4)～5), step 3)～5), step 2)～5) or step 1)～5) synthetic:
1) under-78～25 ℃ of organic solvent neutralization, (S)-epoxy chloropropane (1) and decane metal-salt reagent generation ring-opening reaction under CuI catalysis, obtain the adjacent hydroxy halogeno alkane (2) of long-chain of open loop, compound (2) obtains the epoxy compounds (3) that carbochain prolongs at alkali and alcohol effect ShiShimonoseki ring; Described decane metal-salt reagent is Grignard reagent or metallic lithium reagent, and compound (1) is 1～1.5: 1 with the reaction mol ratio of decane metal-salt reagent, and described CuI is a catalytic amount, 4～10 hours reaction times;
2) in organic solvent and room temperature～60 ℃, the product (3) of step (1) reacted 8-12 hour with NaCN, simultaneously with acid control pH value 10～12, obtain compound (4); Described acid is sulfuric acid, hydrochloric acid, citric acid or acetic acid, and compound (3) is 1: 1～1.5 with the mol ratio of NaCN;
3) product step 2) (4) with hydrogen peroxide reaction 5-12 hour, generates hydrolysate (5) under the effect of organic solvent, 0～100 ℃ and alkali; Compound (4) and H 2O 2, alkali mol ratio be 1: 1～8: 1～8;
4) in organic solvent and room temperature under, carboxylic acid cpd (5) under the thionyl chloride effect with C 1～C 6Pure R 5OH took place condensation reaction 2-12 hour, generated the product (6) of esterification, wherein R 5Represent C 1～C 6Alkyl; Compound (5) is 1: 1～3: 1～20 with the mol ratio of thionyl chloride, alcohol;
5) at organic solvent neutralization-78-0 ℃, compound (6) is under the organic bases effect, with acetic ester CH 3COOR 45-hydroxyl-3-oxo n-Hexadecane acid esters (7) takes place to obtain in condensation reaction 0.5-2 hour; Described organic bases is LDA, LiHMDS or NaHMDS; Described solvent is tetrahydrofuran (THF) or ether, and the mol ratio of described acetic ester, organic bases and compound (6) is 6～1: 6～1: 1; Wherein LDA represents lithium diisopropyl amido, and LiHMDS represents hexamethyl two silica-based amido lithiums, and NaHMDS represents sodium hexamethyldisilazide;
Perhaps in organic solvent and room temperature～60 ℃, compound (4), under activatory zinc and catalyst action with monobromo-acetic acid ester BrCH 2COOR 4The Blaise reaction takes place obtained 5-hydroxyl-3-oxo n-Hexadecane acid esters (7) in 1～8 hour; The mol ratio of described zinc powder, bromacetate, catalyzer and cyano compound (4) is followed successively by 8～1: 4～1: 0～0.01: 1, and described catalyzer is a methanesulfonic, R 4Represent C 1～C 6Alkyl;
Described compound (1)～(6) structural formula is as follows:
Figure FFW00000039940400031
R wherein 5=C 1～C 6Alkyl, compound (7) is as described in the claim 4.
6. method as claimed in claim 5 is characterized in that:
Organic solvent is tetrahydrofuran (THF), toluene, methyl alcohol or ethanol in the described step 1);
Described step 2) organic solvent is methyl alcohol or ethanol in;
Organic solvent is methyl alcohol or ethanol in the described step 3), and described alkali is sodium hydroxide or potassium hydroxide;
Solvent in the described step 4) is methyl alcohol, ethanol or Virahol.
7. the purposes of a compound as claimed in claim 1 or 2 is characterized in that being used to prepare the slimming medicine orlistat.
8. purposes as claimed in claim 7 is characterized in that described preparation slimming medicine orlistat, comprises the steps 1)～3):
1) in organic solvent and 0～20 ℃, idic acid (11) and benzene sulfonyl chloride reaction 1-2 hour generate and close cyclic cpds (12); Compound (11) is 1: 1.5～2 with benzene sulfonyl chloride reaction mol ratio, and reaction system is anhydrous;
2) in organic solvent, under 30～40 ℃ and the 5～20atm pressure, compound (12) is at Pd/C and H 2Catalytic hydrogenation took place 4～12 hours down in effect, generated the compound (13) of deprotection; Described compound (12) is 1: 0.005～0.02 with the mol ratio of Pd;
3) at room temperature, compound (13) and formic acid, aceticanhydride mixture or generated compound (14) in 1～4 hour with arboxylic acid acid anhydride generation formylation reaction; When using formic acid, aceticanhydride mixture, described compound (13) is 1: 1.5～2 with the mol ratio of formic acid, aceticanhydride mixture;
The structural formula of above-mentioned compound (11)～(14) is as follows:
Figure FFW00000039940400041
Figure FFW00000039940400051
CbZ represents carbobenzoxy-(Cbz).
CN2007100417857A 2007-06-08 2007-06-08 2-hexyl-3-hydroxy-5-R1Oxyhexadecanoic acid R2ester, preparation method and application thereof for preparing weight-reducing medicine orlistat Expired - Fee Related CN101066924B (en)

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